Muscle tissue in adult vertebrates regenerates from reserve cells or stem cells or inactive myoblasts called satellite cells. Satellite cells are distributed throughout muscle tissue in close juxtaposition to muscle fibers, and are mitotically quiescent in adult muscle when injury, disease or muscle growth is absent.
Following muscle fiber injury or during the process of recovery from disease, satellite cells re-activate and re-enter the cell cycle. Once activated, the satellite cells proliferate and the daughter cells (progeny cells termed myoblasts) either 1) fuse with existing multinucleated muscle fibers to contribute new nuclei that support muscle growth or regeneration, or 2) fuse with one another to form a new length of multinucleated muscle fiber called a myotube. The new piece (or segment) of a muscle fiber then differentiates into a mature muscle fiber segment that can contract and produce force. If a completely new myotube was formed from the fusion of myoblasts, that myotube then differentiates into a new fiber. The myoblasts therefore ultimately yield replacement muscle fibers or fuse into existing muscle fibers, thereby increasing fiber girth or length or both length and girth. Satellite cells of normal skeletal muscle provide a constant and renewable source of myogenic precursor cells which allows for skeletal muscle repair and regeneration throughout mammalian life.
Nitric oxide (NO), an inorganic free radical, is a versatile biological messenger. Endogenous NO is synthesized from the amino acid L-arginine by three isoforms of the enzyme NO synthase (NOS). Potential pathways of NO signaling in skeletal muscle are reviewed in Anderson and Wozniak (2004) Can. J. Physiol. Pharmacol. 82:300-310, and Wozniak et al. (2005) Muscle & Nerve 31:283-300.
Endogenous NO is a key messenger molecule in the cardiovascular, nervous and immune systems. Research to date has centred largely on the cardiovascular system in which reduced bioavailability of NO is implicated in a range of diseases. A number of NO donors have been used in cardiovascular medicine, including organic nitrates or nitrites, such as amyl nitrite, glyceryl trinitrate and isosorbide dinitrate (ISDN) (see Megson (2000) Drugs of the Future. 25(7):701-715). A compound called vanidil (4-O-(1,2-dinitroglyceryl)-6-nitrovanillic acid) has been synthesized and suggested for use in treating angina (Chen et al. (1991) Gaoxiong Yi Xue Ke Xue Za Zhi. 7(9):476-80).
We previously showed that NO mediates satellite cell activation, and proposed that NO release mediates satellite cell activation possibly via shear-induced rapid increases in NOS activity that produce NO transients; see Anderson (2000) Molec. Biol. Cell 11(5):1859-1874, Tatsumi et al. (2002) Molec. Biol. Cell 13:2909-2918, Anderson and Vargas (2003) Neuromuscular Disorders 13:388-396, and Anderson and Pilipowicz (2002) Nitric Oxide 7:36-41.
Since musculoskeletal health is exquisitely dependent on growth and repair, developing a system to deliver NO to skeletal muscle and thereby manipulate the regulation of satellite cell activation has the potential to promote normal function in injured muscle tissue and possibly be used to treat neuromuscular disease. Furthermore, targeting NO delivery would help avoid side effects in reproductive, vascular and nerve tissue where NO signaling also regulates function.